Staghorn calculi are infrequent and generally are infected stones. Struvite or apatite calculi are embedded with gram-negative bacteria, which can produce endotoxin. Sepsis syndrome may occur after surgical therapy or endoscopic manipulation of infected or staghorn calculi. Sepsis, which can occur despite perioperative antibiotic use, may be due to bacteremia or endotoxemia. We present a child with an infected staghorn calculus who developed overwhelming sepsis and died after percutaneous stone manipulation. Endotoxin assay of stone fragments demonstrated an extremely high level of endotoxin despite low colony bacterial culture growth. This is the first reported case in which endotoxin was demonstrated in stone fragments from a child who died of severe sepsis syndrome after percutaneous staghorn stone manipulation.